Molecular Playground/Insulin

>One of the CBI Molecules being studied in the University of Massachusetts Amherst Chemistry-Biology Interface Program at UMass Amherst in the Roberts Research Group and on display at the Molecular Playground.  Insulin is a hormone that controls carbohydrate metabolism and storage in the human body. The body is able to sense the concentration of glucose in the blood and respond by secreting insulin, which is produced by beta cells in the pancreas. Synthesis of human insulin in E. coli is important to producing insulin for the treatment of type 1 diabetes. Proinsulin (Pins) is processed by several proteases in the Golgi apparatus to form insulin which is shorter by 35 amino acids. DPI is a monomeric despentapeptide (B26-B30) Ins analogue. DTRI is a monomeric destripeptide (B28-B30) Ins analogue. DHPI is for desheptapeptide (B24-B30) Ins. LIns is a legume Ins.

Insulin is made up of two pieces called the A- and B-chain, shown above in blue and green respectively. These two chains are joined by disulfide bonds, which are shown in yellow. This single piece made up of the A- and B-chains is the active form of the insulin hormone. This is the form that binds the insulin receptor on fat or muscle cells in the body, singling them to take up glucose, or sugar, from the blood and save it for later.

Insulin is able to pair-up with itself and form a dimer by forming hydrogen bonds between the ends of two B-chains. These hydrogen bonds are shown above in white. Then, 3 dimers can come together in the presence of zinc ions and form a hexamer. Insulin is stored in the hexameric form in the body. This scene highlights the hydrophobic (gray) and polar (purple) parts of an insulin monomer at a pH of 7. It is believed that the hydrophobic sections on the B-chain cause insulin aggregation which initially caused problems in the manufacture and storage of insulin for pharmaceutical use. 

3D structures of insulin
3i3z, 3i40, 3e7y, 3e7z, 2qiu, 2c8q, 2c8r, 1q4v, 1os3, 1os4, 1mso, 1guj, 1g7a, 1g7b, 1xda, 1trz - hIns A chain + B chain – human 1fu2, 1fub - hIns A chain + B chain – powder diffraction 2kxk, 3bxq, 1b9e – hIns A chain + B chain (mutant)  1zeh - hIns A chain (mutant) + B chain (mutant)  3ir0, 3inc, 3ilg, 3kq6, 3exx, 2r34, 2r35, 2r36 - hIns A chain + B chain + non-Zn metal ion 3fq9, 1xw7, 1rwe, 1jca, 1j73 - hIns A chain (mutant) + B chain 1w8p - hIns A chain + B chain (mutant)  2w44 - hIns A chain residues 82-98 + B chain residues 25-53 2wru, 2wrv, 2wrw, 2wrx, 2ws0, 2ws1, 2ws4, 2ws6, 2ws7, 1qj0 - hIns A chain + B chain residues 25-54 (mutant)  3jsd, 2vjz, 2vk0, 1uz9 - hIns A chain residues 90-110 + B chain residues 25-54

3gky, 2g4m, 1zni, 1znj, 1wav, 1iza, 1izb, 9ins, 4ins, 3ins - pIns A chain + B chain – pig 2zpp, 2efa - pIns A chain + B chain – Neutron 2zp6, 1aph, 1bph, 1cph, 1dph - bIns A chain + B chain – bovine<BR /> 2a3g, 2bn1, 2bn3 - bIns A chain residues 85-105 + B chain residues 25-54

3rto, 3fhp - pIns A chain residues 88-108 + B chain residues 25-54

1m5a - pIns A chain + B chain + non-Zn metal ion<BR /> 6ins – pins single chain

Insulin structures using NMR
1sf1, 2aiy, 3aiy, 4aiy, 5aiy, 1ai0, 1aiy, 1xgl, 1hiq, 1hit - hIns A chain + B chain – NMR<BR /> 2hiu – apo-hIns A chain + B chain – NMR<BR /> 2kqq, 1t1k, 1t1p, 1t1q - hIns A chain (mutant) + B chain – NMR<BR /> 2jmn, 2h67, 2hh4, 2hho, 1jco, 1a7f - hIns A chain + B chain (mutant) – NMR<BR /> 2jum, 2juu, 2juv, 1kmf, 1k3m, 1bzv, 1vkt, 1hui, 1mhi, 1mhj, 1hls - hIns A chain (mutant) + B chain (mutant) – NMR<BR /> 2kjj, 2kju, 2k91, 2k9r, 2rn5 - hIns A chain residues 90-110 + B chain residues 25-54 (mutant) – NMR<BR /> 1lkq - hIns A chain residues 90-110 (mutant) + B chain residues 25-54 (mutant) – NMR<BR /> 2jv1 – apo-hIns A chain residues 90-110 + B chain residues 25-54 (mutant) – NMR<BR /> 2jzq - hIns A chain – NMR<BR /> 1ho0 - hIns B chain (mutant) – NMR<BR />

Insulin binary complexes
3brr - hIns A chain + B chain + sulfatide<BR /> 1ben - hIns A chain + B chain + hydroxybenzamide<BR /> 1tyl, 1tym - hIns A chain + B chain + hydroxyacetanilide<BR /> 2oly, 2om0, 2omh, 2omi - hIns A chain + B chain + urea + resorcinol<BR /> 2omg - hIns A chain + B chain + urea + cresol

2olz, 2om1 - hIns A chain + B chain + thiocyanate<BR /> 1jk8 - hIns B chain peptide + HLA<BR /> 1zeg, 1lph - hIns A chain (mutant) + B chain (mutant) + phenol

1qiy - hIns A chain + B chain residues 25-54 (mutant) + phenol

1qiz - hIns A chain + B chain residues 25-54 (mutant) + resorcinol<BR /> 1ev3, 1ev6 - hIns A chain residues 87-107 + B chain residues 25-54+ cresol

1evr - hIns A chain residues 87-107 + B chain residues 25-54+ resorcinol<BR /> 3q6e - hIns A chain residues 90-110 + B chain residues 25-54+ synthetic receptor<BR /> 1b17, 1b18, 1b19, 1b2a, 1b2b, 1b2c, 1b2d, 1b2e, 1b2f, 1b2g - pIns A chain + B chain + sulfate<BR /> 1mpj - pIns A chain + B chain + phenol

2tci - pIns A chain + B chain + thiocyanate<BR /> 3mth - pIns A chain + B chain + methylparaben<BR /> 1zei - pIns A chain (mutant) + cresol

7ins - pIns A chain + B chain + clupeine + cresol

Proinsulin
2kqp – hPIns A chain – NMR<BR /> 1t0c - hPIns A chain residues 57-87 – NMR<BR /> 1iog, 1ioh, 1sjt - hPIns A chain (mutant) + B chain (mutant) – NMR<BR /> 1efe – mini-hPIns<BR /> 1sju - mini-hPIns (mutant)

Despeptide insulin
2ceu – DPI – yeast<BR /> 1sdb - pDPI A chain + B chain<BR /> 1pid - bDPI A chain + B chain<BR /> 1his - hDPI A chain + B chain]] - NMR<BR /> 1htv – hDTRI A chain + B chain<BR /> 1dei – pDHPI A chain (mutant) + B chain (mutant) <BR /> 2ins – bD-Phe Ins chain A + chain B

Leginsulin
1ju8 – Lins A chain residues 1-37 – legume - NMR<BR />

Additional Resources
For additional information, see: Diabetes & Hypoglycemia